FAK (Focal Adhesion Kinase) is a nonreceptor tyrosine kinase which transduces signaling from a group of stimuli (e.g., integrins, cytokines, chemokines, and growth factors) to control a variety of cellular pathways and processes, including cell proliferation, migration, morphology, and cell survival. FAK is activated by FAC (focal adhesion complex)-associated growth factors and integrins. The binding to integrins of EMC (extracellular matrix) leads to the activation of FAK. The activation of FAK can be further enhanced by co-stimulation of the growth factors by ECM associated growth factors, such as bFGF, EGF or PDGF. Focal adhesion complex assembly and disassembly are essential for cell attachment and movement. FAK doesn't phosphorylate other proteins. However, activated FAK autophosphorylates and binds Src kinase which in turn phosphorylate other sites of FAK and other FAK binding proteins such as Cas and paxillin. Phosphorylated FAK provides the docking site for mediators of multiple signaling events and consequently involves in the regulation of cell growth and survival through activation of PI3K/Akt/mTOR and Grb2/SOS/RAS/Raf/MEK/ERK pathways. Overexpression of FAK has been associated with malignancy in a variety of cancers. Inhibition of FAK has been shown the inhibition of tumor growth in different cancer cells (Beviglia et al 2003, BioChem J. 373: 201-210, Smith et al 2005, Melanoma Res. 15:357-362, Haider et al 2005, Clin. Cancer Res. 11: 8829-8836, van Nimwegen et al 2005, Cancer Res. 65:4698-4706, Mitra et al 2006, Oncogene 25: 4429-4440). However, inhibition of FAK in normal human fibrolasts or immortalized mammary cells didn't cause loss of attachment or apoptosis (Xu et al 1996 Cell Growth and Diff. 7: 413-418). Furthermore, loss of FAK activity (reconstitution of FAK−/−cells with kinase-dead FAK) reduced growth of v-Src tumors in mice and decreased angiogenesis. Therefore, Inhibition of FAK is a potential therapy for the treatment of hyper-proliferative diseases such as cancers.
Pyk2 is the only member of the FAK family with 48% amino acid identity. Although the role of Pyk2 in tumorigenesis is not well-established yet, there is some evidence that Pyk2 plays a compensatory role FAK knockout mouse model. Therefor, dual inhibition of FAK and Pyk2 may considerably augment the anti-angiogenic effect.